Johannesburg, South Africa
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Hagan H.,University of South Africa | Hagan H.,New York University | Pouget E.R.,National Development and Research Institutes | Williams I.T.,Centers for Disease Control and Prevention | And 6 more authors.
Journal of Infectious Diseases | Year: 2010

Background. In studies of hepatitis C virus (HCV) seroconversion in injection drug users (IDUs), some have questioned whether underreporting of syringe sharing, a stigmatized behavior, has led to misattribution of HCV risk to other injection-related behaviors. Methods. IDUs aged 15-30 years who were seronegative for human immunodeficiency virus and HCV antibodies were recruited into a prospective study in 5 US cities. Behavioral data were collected via computer-assisted self-interviewing to reduce socially desirable reporting. Hazard ratios (HRs) were estimated to assess associations between behavior and HCV seroconversion. Because the shared use of cookers, cottons, and rinse water was highly correlated, a summary variable was created to represent drug preparation equipment sharing. Results. Among 483 IDUs who injected during the period covered by the follow-up assessments, the incidence of HCV infection was 17.2 cases per 100 person years; no HIV seroconversions occurred. Adjusting for confounders, the shared use of drug preparation equipment was significantly associated with HCV seroconversion (adjusted HR, 2.66; 95% confidence interval, 1.03-23.92), but syringe sharing was not (adjusted HR, 0.91). We estimated that 37% of HCV seroconversions in IDUs were due to the sharing of drug preparation equipment. Conclusions. Associations between sharing drug preparation equipment and HCV seroconversion are not attributable to underascertainment of syringe sharing. Avoiding HCV infection will require substantial reductions in exposure to all sources of contaminated blood. © 2010 by the Infectious Diseases Society of America. All rights reserved.


Ferguson L.,London School of Hygiene and Tropical Medicine | Ferguson L.,University of Nairobi | Lewis J.,London School of Hygiene and Tropical Medicine | Lewis J.,Aurum Institute for Health Research | And 6 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2012

Background: There has been little attention, until recently, to linking women who test HIV positive in pregnancy-related services to long-term HIV care and treatment services. Methods: A retrospective review of routine hospital data was carried out in 2 hospitals in Kenya. Associations between available demographic information and uptake of HIV-related services within 6 months of HIV diagnosis in pregnancy-related services were assessed using logistic regression. Kaplan-Meier survival analysis was used to assess time between HIV diagnosis and registration at the HIV clinic. Referrals between pregnancy-related and HIV-related services were observed. Results: At Naivasha hospital, the proportion of women registering at the HIV clinic within 6 months was 17.2% (153 of 892); at Gilgil hospital, it was 35.4% (84 of 237). Highly active antiretroviral therapy (HAART) was initiated by 40% and 27% of known eligible women in Naivasha and Gilgil, respectively. Non-systematic registration of clients on first contact at the HIV clinic, and restricted availability of services due to costs and opening hours were observed. In Naivasha, year, attendance at multiple pregnancy-related visits, and attendance at antenatal care in Naivasha hospital were associated with registration at the HIV clinic. In Gilgil, year, attendance at multiple pregnancy-related visits, and women being in their first pregnancy were associated with the outcome. Conclusions: Only 4% of women estimated to need HAART for their own care initiated HAART within 6 months of HIV diagnosis. Challenges associated with providing longitudinal care are especially evident in the context of high population mobility. Innovation in service delivery is required to improve uptake of services. © 2012 Lippincott Williams & Wilkins.


Gray G.E.,University of Witwatersrand | Gray G.E.,South African Medical Research Council | Moodie Z.,Fred Hutchinson Cancer Research Center | Metch B.,Fred Hutchinson Cancer Research Center | And 15 more authors.
The Lancet Infectious Diseases | Year: 2014

Background: The HVTN 503/Phambili study, which assessed the efficacy of the Merck Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine in South Africa, was stopped when futility criteria in the Step study (assessing the same vaccine in the Americas, Caribbean, and Australia) were met. Here we report long-term follow-up data. Methods: HVTN 503/Phambili was a double-blind, placebo-controlled, randomised trial that recruited HIV-1 uninfected, sexually active adults aged 18-35 years from five sites in South Africa. Eligible participants were randomly assigned (1:1) by computer-generated random numbers to either vaccine or placebo, stratified by site and sex. Cox proportional hazards models were used to estimate HIV-1 infection in the modified intention-to-treat cohort, all of whom were unmasked early in follow-up. The trial is registered with ClinicalTrials.gov, number NCT00413725 and the South African National Health Research Database, number DOH-27-0207-1539. Findings: Between Jan 24, 2007, and Sept 19, 2007, 801 participants (26·7%) of a planned 3000 were randomly assigned (400 to vaccine, 401 to placebo); 216 (27%) received only one injection, 529 (66%) received only two injections, and 56 (7%) received three injections. At a median follow-up of 42 months (IQR 31-42), 63 vaccine recipients (16%) had HIV-1 infection compared with 37 placebo recipients (9%; adjusted HR 1·70, 95% CI 1·13-2·55; p=0·01). Risk for HIV-1 infection did not differ according to the number of vaccinations received, sex, circumcision, or adenovirus type 5 (Ad5) serostatus. Differences in risk behaviour at baseline or during the study, or annualised dropout rate (7·7% [95% CI 6·2-9·5] for vaccine recipients vs 8·8% [7·1-10·7] for placebo recipients; p=0·40) are unlikely explanations for the increased rate of HIV-1 infections seen in vaccine recipients. Interpretation: The increased risk of HIV-1 acquisition in vaccine recipients, irrespective of number of doses received, warrants further investigation to understand the biological mechanism. We caution against further use of the Ad5 vector for HIV vaccines. Funding: National Institute of Allergy and Infectious Diseases, Merck, and South African Medical Research Council. © 2014 Elsevier Ltd.


Getahun H.,World Health Organization | Kittikraisak W.,Centers for Disease Control and Prevention | Heilig C.M.,Centers for Disease Control and Prevention | Corbett E.L.,London School of Hygiene and Tropical Medicine | And 14 more authors.
PLoS Medicine | Year: 2011

Background: The World Health Organization recommends the screening of all people living with HIV for tuberculosis (TB) disease, followed by TB treatment, or isoniazid preventive therapy (IPT) when TB is excluded. However, the difficulty of reliably excluding TB disease has severely limited TB screening and IPT uptake in resource-limited settings. We conducted an individual participant data meta-analysis of primary studies, aiming to identify a sensitive TB screening rule. Methods and Findings: We identified 12 studies that had systematically collected sputum specimens regardless of signs or symptoms, at least one mycobacterial culture, clinical symptoms, and HIV and TB disease status. Bivariate random-effects meta-analysis and the hierarchical summary relative operating characteristic curves were used to evaluate the screening performance of all combinations of variables of interest. TB disease was diagnosed in 557 (5.8%) of 9,626 people living with HIV. The primary analysis included 8,148 people living with HIV who could be evaluated on five symptoms from nine of the 12 studies. The median age was 34 years. The best performing rule was the presence of any one of: current cough (any duration), fever, night sweats, or weight loss. The overall sensitivity of this rule was 78.9% (95% confidence interval [CI] 58.3%-90.9%) and specificity was 49.6% (95% CI 29.2%-70.1%). Its sensitivity increased to 90.1% (95% CI 76.3%-96.2%) among participants selected from clinical settings and to 88.0% (95% CI 76.1%-94.4%) among those who were not previously screened for TB. Negative predictive value was 97.7% (95% CI 97.4%-98.0%) and 90.0% (95% CI 88.6%-91.3%) at 5% and 20% prevalence of TB among people living with HIV, respectively. Abnormal chest radiographic findings increased the sensitivity of the rule by 11.7% (90.6% versus 78.9%) with a reduction of specificity by 10.7% (49.6% versus 38.9%). Conclusions: Absence of all of current cough, fever, night sweats, and weight loss can identify a subset of people living with HIV who have a very low probability of having TB disease. A simplified screening rule using any one of these symptoms can be used in resource-constrained settings to identify people living with HIV in need of further diagnostic assessment for TB. Use of this algorithm should result in earlier TB diagnosis and treatment, and should allow for substantial scale-up of IPT.


Churchyard G.J.,Aurum Institute for Health Research | Churchyard G.J.,London School of Hygiene and Tropical Medicine | Fielding K.L.,London School of Hygiene and Tropical Medicine | Lewis J.J.,London School of Hygiene and Tropical Medicine | And 4 more authors.
AIDS | Year: 2010

Objective: This analysis describes the prevalence of and risk factors for tuberculosis at screening prior to isoniazid preventive therapy (IPT); the additional yield of tuberculosis using chest radiography versus symptoms alone, and risk factors for tuberculosis missed by screening. Design: Cross-sectional analysis of a trial of community-wide IPT in South African gold mines. Methods: Participants were screened for tuberculosis prior to starting IPT using symptoms (cough >2 weeks, weight loss, night sweats) and chest radiography. Tuberculosis suspects had sputum collected for mycobacterial investigations. Those with a positive smear or culture with no speciation or culture identified as Mycobacterium tuberculosis were classified as having probable or definite tuberculosis, respectively. Among participants who were dispensed IPT, we defined a 'missed' case of active tuberculosis as one identified within 90 days of the enrolment screen. Results: Between July 2006 and December 2008, among 23 286 participants with complete data, the prevalence of undiagnosed tuberculosis [definite (284) and probable (31)] was high (315/23 286; 1.4%). The addition of chest radiography to symptom screening increased the number of definite tuberculosis cases detected by 2.5-fold (113 to 281 cases). Among 19 609 individuals correctly screened for tuberculosis who started IPT and had more than 90 days of follow-up, only 39 (0.2%) active tuberculosis cases were missed. Risk factors for tuberculosis missed by screening included increasing age [adjusted odds ratio (aOR) 1.66/10 year increase, 95% confidence interval (CI) 1.07-2.56], non-South African, in HIV care (aOR 4.80, 95% CI 1.63-14.1), lower weight (aOR 2.07/10 kg decrease, 95% CI 1.23-3.49) and alcohol use (aOR 2.52, 95% CI 1.31-4.86), which were similar to risk factors for tuberculosis detected by screening. Conclusion: Tuberculosis screening prior to IPT detects a substantial burden of tuberculosis and misses very few cases. Chest radiography significantly increased the yield of tuberculosis cases detected. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Chihota V.N.,Aurum Institute for Health Research | Grant A.D.,London School of Hygiene and Tropical Medicine | Fielding K.,London School of Hygiene and Tropical Medicine | Ndibongo B.,Aurum Institute for Health Research | And 5 more authors.
International Journal of Tuberculosis and Lung Disease | Year: 2010

SETTING: National Health Laboratory Services tuberculosis (TB) laboratory, South Africa. OBJECTIVES: To compare Mycobacterium Growth Indicator Tube (MGIT) with Löwenstein-Jensen (LJ) medium with regard to Mycobacterium tuberculosis yield, time to positive culture and contamination, and to assess MGIT cost-effectiveness. DESIGN: Sputum from gold miners was cultured on MGIT and LJ. We estimated cost per culture, and, for smear-negative samples, incremental cost per additional M. tuberculosis gained with MGIT using a decision-tree model. RESULTS: Among 1267 specimens, MGIT vs. LJ gave a higher yield of mycobacteria (29.7% vs. 22.8%), higher contamination (16.7% vs. 9.3%) and shorter time to positive culture (median 14 vs. 25 days for smear-negative specimens). Among smear-negative samples that were culture-positive on MGIT but negative/contaminated on LJ, 77.3% were non-tuberculous mycobacteria (NTM). Cost per culture on LJ, MGIT and MGIT+LJ was respectively US$12.35, US$16.62 and US$19.29. The incremental cost per additional M. tuberculosis identified by standard biochemical tests and microscopic cording was respectively US$504.08 and US$328.10 using MGIT vs. LJ, or US$160.80 and US$109.07 using MGIT+LJ vs. LJ alone. CONCLUSION: MGIT gives higher yield and faster results at relatively high cost. The high proportion of NTM underscores the need for rapid speciation tests. Minimising contaminated cultures is key to cost-effectiveness. © 2010 The Union.


Grant A.D.,London School of Hygiene and Tropical Medicine | Mngadi K.T.,Aurum Institute for Health Research | Van Halsema C.L.,London School of Hygiene and Tropical Medicine | Luttig M.M.,Aurum Institute for Health Research | And 3 more authors.
AIDS | Year: 2010

Objectives: We describe isoniazid-related adverse events in Thibela TB, a cluster-randomized study of community-wide isoniazid preventive therapy (IPT) among gold miners in South Africa, where HIV prevalence is estimated at 30%. Methods: Consenting employees were screened prior to IPT for active tuberculosis and increased risk of isoniazid toxicity using a questionnaire and chest radiograph. Study-defined IPT-related adverse events were sought at each study visit: liver function tests were only performed if clinically indicated. In a substudy, we questioned consecutive participants at baseline and months 1, 3, and 6 concerning minor IPT-related adverse events. Results: Among 24 221 participants (95.2% men, median age 40 years), 130 individuals had 132 study-defined adverse events (0.54%); 61 (0.25%) possible hypersensitivity rash, 50 (0.21%) peripheral neuropathy, 17 (0.07%) clinical hepatotoxicity, and four (0.02%) convulsions. Four events (two hepatotoxicity, one fatal, and two convulsions) fulfilled criteria for seriousness. Clinical hepatotoxicity was associated with consumption of alcohol [0.11 vs. 0.03% if no alcohol consumed, odds ratio 3.9 (95% confidence interval 1.2-12.1)], but not with sex, age, weight, or concurrent antiretroviral therapy. In the substudy, 324 of 498 (65.1%) participants reported better health since starting IPT; 180 of 324 (55.6%) reported that this was because of increased appetite. The frequency of specific minor symptoms was low among those taking IPT, and all symptoms were reported less often than at baseline. Conclusion: The risk of adverse events, particularly hepatotoxicity, was very low in this population. Our data suggest that clinical criteria can safely be used for screening prior to and monitoring during IPT. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Lawn S.D.,Institute for Infectious Disease and Molecular Medicine | Lawn S.D.,London School of Hygiene and Tropical Medicine | Wood R.,Institute for Infectious Disease and Molecular Medicine | Kranzer K.,Institute for Infectious Disease and Molecular Medicine | And 6 more authors.
The Lancet Infectious Diseases | Year: 2010

Antiretroviral therapy and isoniazid preventive therapy (IPT) are both effective interventions to prevent HIV-associated tuberculosis, but work via different mechanisms. We propose that these two interventions might best be used as complementary strategies at different stages of HIV progression. At relatively high CD4-cell counts, IPT reduces tuberculosis risk by 64% (95% CI 39-78%) in patients with positive tuberculin skin tests, and is the key tuberculosis preventive intervention before patients are eligible for antiretroviral therapy. However, at low CD4-cell counts, reliable exclusion of active tuberculosis is difficult, fewer patients are eligible for IPT, and waning immune function might limit the durability of its effect. In such patients, antiretroviral therapy is the primary intervention needed, reducing tuberculosis incidence by 67% (95% CI 61-73%). However, tuberculosis risk during long-term antiretroviral therapy remains several times higher than background, especially in those with poor immune recovery. Patients might therefore derive additional benefit from combined use of IPT and antiretroviral therapy to simultaneously treat mycobacterial infection and restore tuberculosis-specific immune function. For those first presenting with advanced immunodeficiency, we propose that concurrent IPT might best be delayed until completion of the first few months of antiretroviral therapy, when active tuberculosis can be more reliably excluded. Data from randomised controlled trials are needed to underpin further development of public-health policy. © 2010 Elsevier Ltd. All rights reserved.


Ross J.,Columbia University | Ehrlich R.I.,University of Cape Town | Hnizdo E.,U.S. National Institute for Occupational Safety and Health | White N.,University of Cape Town | And 2 more authors.
Thorax | Year: 2010

Background: Few if any studies of the association between pulmonary tuberculosis (TB) and lung function loss have had access to premorbid lung function values. Methods: Using a retrospective cohort design, the study recruited employed South African gold miners who had undergone a pulmonary function test (PFT) between January 1995 and August 1996. The 'exposed' group comprised 185 miners treated for pulmonary TB after the initial PFT and the 'unexposed' group comprised 185 age-matched miners without TB. All participants had a follow-up PFT between April and June 2000. The outcome of interest was decline in lung function during the follow-up period as measured by forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). Results: After controlling for age, height, baseline lung function, silicosis, years of employment, smoking and other respiratory diagnoses, pulmonary TB during the follow-up period was associated with a mean excess loss of 40.3 ml/year in FEV1 (95% CI 25.4 to 55.1) and 42.7 ml/year in FVC (95% CI 27.0 to 58.5). Lung function loss was greater among those with more severe or later clinical presentation of TB. Breathlessness was twice as common among TB cases (OR 2.20, 95% CI 1.18 to 4.11). Conclusion: There is a need for greater clinical recognition of the long-term respiratory consequences of treated pulmonary TB. Early detection of TB would help to reduce these sequelae and remains a priority, particularly in a workforce already subject to silica dust disease. However, strategies such as dust control, worker education about TB and dust and TB preventive therapy are also needed to avert the disease itself.


Ehrlich R.I.,University of Cape Town | Myers J.E.,University of Cape Town | Te Water Naude J.M.,Asbestos Relief Trust | Thompson M.L.,University of Cape Town | And 2 more authors.
Occupational and Environmental Medicine | Year: 2011

Objective: To estimate exposure-response relationships between respirable dust, respirable quartz and lung function loss in black South African gold miners. Methods: 520 mineworkers aged >37 years were enrolled in a cross-sectional study. Gravimetric dust measurements were used to calculate cumulative respirable dust and quartz exposures. Excess lung function loss was defined as predicted minus observed forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). The association between excess loss and exposure was estimated, adjusting for smoking, tuberculosis and silicosis. Results: Mean service length was 21.8 years, mean respirable dust 0.37 mg/m3 and mean respirable quartz 0.053 mg/m3. After adjustment, 1 mg-yr/m3 increase in cumulative respirable dust exposure was associated with 18.7 ml mean excess loss in FVC [95% confidence interval (CI) 0.3, 37.1] and 16.2 ml in FEV1 (95% CI -0.3, 32.6). Mean excess loss with silicosis was 224.1 ml in FEV1 and 123.6 ml in FVC; with tuberculosis 347.4 ml in FEV1 and 264.3 ml in FVC. Conclusion: Despite a healthy worker effect, lung function loss was demonstrable whether due to silicosis, tuberculosis or an independent effect of dust. A miner working at a respirable dust intensity of 0.37 mg/m3 for 30 years would lose on average an additional 208 ml in FVC (95% CI 3, 412) in the absence of other disease, an impact greater than that of silicosis and comparable to that of tuberculosis. Improved dust control on the South African gold mines would reduce the risk of silicosis, tuberculosis and lung function impairment.

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